7-128830652-C-A

Variant names:

• chr7-128830652-C-A
• rs759632330
• NM_001458.5:c.15C>A

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_001458.5(FLNC):​c.15C>A​(p.Ser5Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000116 in 1,459,926 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S5G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: FLNC NM_001458.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 2.16
• Publications: 1 publications found

Genes affected

FLNC (HGNC:3756): (filamin C) This gene encodes one of three related filamin genes, specifically gamma filamin. These filamin proteins crosslink actin filaments into orthogonal networks in cortical cytoplasm and participate in the anchoring of membrane proteins for the actin cytoskeleton. Three functional domains exist in filamin: an N-terminal filamentous actin-binding domain, a C-terminal self-association domain, and a membrane glycoprotein-binding domain. Mutations in this gene are a cause of cardiopathy. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2022]

FLNC Gene-Disease associations (from GenCC):

• dilated cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen, Ambry Genetics, G2P
• myofibrillar myopathy 5

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, G2P
• hypertrophic cardiomyopathy 26

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
• distal myopathy with posterior leg and anterior hand involvement

  Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics
• familial isolated restrictive cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• heart conduction disease

  Inheritance: AD Classification: LIMITED Submitted by: Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.13208804).
• BP6: Variant 7-128830652-C-A is Benign according to our data. Variant chr7-128830652-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 539382.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.
• BS2: High AC in GnomAdExome4 at 17 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLNC	NM_001458.5	c.15C>A	p.Ser5Arg	missense_variant	Exon 1 of 48	ENST00000325888.13	NP_001449.3
FLNC	NM_001127487.2	c.15C>A	p.Ser5Arg	missense_variant	Exon 1 of 47		NP_001120959.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLNC	ENST00000325888.13	c.15C>A	p.Ser5Arg	missense_variant	Exon 1 of 48	1	NM_001458.5	ENSP00000327145.8

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000494 AC: 12 AN: 242844 AF XY: 0.0000375

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000184

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000116 AC: 17 AN: 1459926 Hom.: 0 Cov.: 32 AF XY: 0.0000124 AC XY: 9 AN XY: 726262

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.000246 AC: 11 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51848

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111800

Other (OTH) AF: 0.0000166 AC: 1 AN: 60294

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000166 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Feb 12, 2025

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in a patient with HCM in published literature (PMID: 37466024); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 37466024) -

Cardiovascular phenotype Uncertain:1

Mar 31, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.S5R variant (also known as c.15C>A), located in coding exon 1 of the FLNC gene, results from a C to A substitution at nucleotide position 15. The serine at codon 5 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Myofibrillar myopathy 5;C3279722:Distal myopathy with posterior leg and anterior hand involvement;C4310749:Hypertrophic cardiomyopathy 26;CN239310:Dilated Cardiomyopathy, Dominant Benign:1

Nov 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.24	T;.
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.79	T;T
M_CAP	Pathogenic	0.63	D
MetaRNN	Benign	0.13	T;T
MetaSVM	Benign	-0.31	T
MutationAssessor	Benign	0.0	N;N
PhyloP100		2.2
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-1.1	N;N
REVEL	Benign	0.17
Sift	Benign	0.063	T;T
Sift4G	Benign	0.17	T;T
Polyphen		0.0030	B;B
Vest4		0.14
MutPred		0.28		Gain of solvent accessibility (P = 0.0171);Gain of solvent accessibility (P = 0.0171);
MVP		0.46
MPC		1.1
ClinPred		0.065	T
GERP RS		3.1
PromoterAI		-0.018	Neutral
Varity_R		0.20
gMVP		0.71
Mutation Taster		=84/16	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs759632330; hg19: chr7-128470706;